title: Therapeutic efficacy of 177Lu-CHX-A''-DTPA-hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy.
abstract: BACKGROUND
  This study investigated the biodistribution and therapeutic efficacy of Lutetium-177 (177Lu) radiolabeled anti-Lewis Y monoclonal antibody hu3S193 radioimmunotherapy (RIT) in mice bearing prostate cancer xenografts. The ability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 and docetaxel chemotherapy to enhance the efficacy of RIT was also assessed in vivo.
  
  
  METHODS
  The in vitro cytotoxicity of 177Lu labeled hu3S193 on Le(y) positive DU145 prostate cancer cells was assessed using proliferation assays, with induction of apoptosis measured by ELISA. The in vivo biodistribution and tumor localization of 177Lu-hu3S193 was assessed in mice bearing established DU145 tumor xenografts. The efficacy and maximum tolerated dose of 177Lu-hu3S193 RIT in vivo was determined by a dose escalation study. EGFR inhibitor AG1478 or docetaxel chemotherapy was administered at sub-therapeutic doses in conjunction with RIT in vivo.
  
  
  RESULTS
  177Lu-hu3S193 mediated significant induction of cytotoxicity and apoptosis in vitro. In vivo analysis of 177Lu-hu3S193 biodistribution demonstrated specific targeting of DU145 prostate cancer xenografts, with maximal tumor uptake of 33.2 +/- 3.9%ID/g observed at 120 hr post-injection. In RIT studies, 177Lu-hu3S193 caused specific and dose-dependent inhibition of prostate cancer tumor growth. A maximum tolerated dose of 350 microCi was determined for 177Lu-hu3S193. Combination of 177Lu-hu3S193 RIT with EGFR inhibitor AG1478 or docetaxel chemotherapy both significantly improved efficacy.
  
  
  CONCLUSIONS
  177Lu-hu3S193 RIT is effective as a single agent in the treatment of Le(y) positive prostate cancer models. The enhancement of RIT by AG1478 or docetaxel indicates the promise of combined modality strategies.
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research, Melbourne Centre for ClinicalSciences, Austin Hospital, Heidelberg, Victoria, Australia. mpkelly2@hotmail.com
authors.forename: Marcus P
authors.initials: MP
authors.lastname: Kelly
authors.forename: Sze Ting
authors.initials: ST
authors.lastname: Lee
authors.forename: F-T
authors.initials: FT
authors.lastname: Lee
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Smyth
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D000077143:Docetaxel; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates; D008187:Lutetium / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D004369:Pentetic Acid / Q000031:analogs & derivatives; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000627:therapeutic use; D043823:Taxoids / Q000627:therapeutic use*; D020032:Tyrphostins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C522039:Hu3S193 monoclonal antibody; D017879:Isothiocyanates; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D011868:Radioisotopes; D043823:Taxoids; D020032:Tyrphostins; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D000077143:Docetaxel; C101044:RTKI cpd; D008187:Lutetium; D004369:Pentetic Acid; D066246:ErbB Receptors